The invention relates to new microparticles, pharmaceutical agents containing them, their use, e.g., in ultrasonic diagnosis as well as processes for the production of these microparticles and pharmaceutical agents.
It is known that by peripheral injection of solutions, which contain fine gas bubbles, cardiac echo contrasts can be achieved (Roelandt J., Ultrasound Med. Biol. 8: 471-492, 1982). These air bubbles are obtained in physiologically compatible solutions, e.g., by shaking, other agitation or by addition of carbon dioxide. But they are not uniform in regard to number and size and can be reproduced only unsatisfactorily. Also they generally are not stabilized so that their life is short. Their average diameters in most cases are above the size of erythrocytes so that no lung capillary passage with subsequent contrasting of organs such as left heart, liver, kidney or spleen is possible. Further, they are not suitable for quantifications, since the ultrasound echo produced by them is composed of several inseparable processes such as bubble formation, coalescence and dissolution. Thus, e.g., it is not possible with these ultrasonic contrast media to obtain displays on transit times by the measurement of the contrast course in the myocardium.
The stabilization of the gas bubbles by sugar is described in EP 0 131 540. Thus the reproducibility and homogeneity of the contrast effect is indeed improved but these bubbles do not survive a lung passage.
It is described in EP 0 122 624 and 0 123 235 that the gas bubble stabilizing effect of sugars, sugar alcohols and salts is improved by addition of surfactants. A lung capillary passage and the possibility of representation of the arterial vessel branch and different organs such as liver and spleen exists with this ultrasonic contrast media. But here the contrast effect is limited to the vessel lumen, since the bubbles are not absorbed by the tissue cells.
None of the ultrasonic contrast media known so far remains unchanged for a prolonged period in the body. Therefore an organ representation with sufficient signal intensity by selective concentration after i.v. injection or quantifications are not possible.
An encapsulation of gases, such as, for example, air as ultrasonic contrast media, is described in DE-OS 38 03 972. The wall material used here consists of biodegradable synthetic material, such as especially cyanoacrylate and polylactide.
But these microparticles--especially on larger scale as well as in regard to their working up--are difficult to produce. Thus especially the broad size distribution of these particles is a drawback.